Viral hepatitis such as hepatitis B is an important and major disease threatening the life and health of people, and the fundamental approach for treatment of hepatitis B is an antiviral treatment. At present, clinically effective drugs against hepatitis B virus are mainly interferons and lamivudine. However, the effective rate of interferon treatment is merely 30-50%, and has dose-dependent toxicity and side-effects. Lamivudine has pronounced activity against hepatitis B virus, but may result in drug resistance during long-term administration. After consecutive administration for 2 years, the incidence rate of drug resistance is up to 40-50%, thereby inducing serious consequences such as acute episode of hepatitis.
Nucleotide analogues are not phosphorylated in cells, and thus can overcome the drug resistance of lamivudine, and do not generate drug resistance per se. Adefovir dipivoxil as one of the representative drugs had been approved for marketing in Europe and the United States. However, Adefovir dipivoxil has certain cytotoxicity, and may produce nephrotoxicity during clinical use. In addition, similar to lamivudine, after drug withdrawal of Adefovir dipivoxil, replication rebound of hepatitis B virus may occur and induce the recurrence of hepatitis B.
According to the successful experiences in the research of anti-HIV drugs, COCKTAIL treatment of using drugs in combination can effectively overcome drug resistance and accelerate the clearance of virus. The number of people with infection of hepatitis B is 10 times or more the number of people with HIV infection, but the clinically effective drugs against hepatitis B virus are few.
European patent EP0785208 discloses a series of acyclic nucleoside phosphonate compounds of the following formula:
                wherein, R1 represents a substituent for occurrence once such as an alkoxy, and alkyl; R2 represents hydrogen or an alkyl, R3 and R4 represent hydrogen, and an alkyl, etc. Among them, the compound 2-amino-6-(4-methoxyphenylthio)-9-[2-[bis(2,2,2-trifluoroethyloxy)phosphono methoxy]propyl]-purine (MCC-478, Alamifovir) has been clinically investigated.        

MCC-478 is a nucleotide with a new structure and is a new drug against hepatitis B virus. In the chemical structure, it is different from those known nucleosides as anti-hepatitis B drugs. MCC-478 molecule has a modified glycosyl and is further substituted with phenylthio at position-6 of nucleoside base mother nucleus. In pharmaceutical properties, MCC-478 also exhibits features different from other anti-HBV drugs, i.e., it inhibits the replication of viruses by inhibiting the initiating reaction and assembling reaction of protein synthesis (Clark Chan, et al. Clinical Pharmacokinetics of Alamifovir and Its Metabolites. Antivicrob Agents Chemother, 2005, 49(5):1813-1822); it has high selectivity and inhibition effect to HBV, and its in vitro activity is 20-80 times that of lamivudine, and 10-20 times that of adefovir. However, it has no activity against other retro viruses such as HIV and HSV (Kamiya N, et al. Antiviral activities of MCC-478, a novel and specific inhibitor of hepatitis B Virus. Antimicrob Agents Chemother 2002; 46(9):2872), thereby exhibiting unique pharmacological properties; MCC-478 also has inhibition effects on HBV strains with resistance to lamivudine (Suzane Kioko Ono-Nita, Oro-Nita S K, et al. Novel Nucleoside analogue MCC-478 (LY582563) is effective against wild-type or lamivudine-resistant hepatitis B virus. Antimicrob Agents Chemother 2002; 46: 2602-2605).
As a prodrug of the nucleotide analogue, MCC-478 releases the free acid (602076) and produces the effect against virus after entering the body and being hydrolyzed, but the results of pharmacokinetics showed that the major metabolite of MCC-478 in human body is nucleotide monoester (602074), the concentration of the free acid 602076 in blood is merely 1/10 of that of the monoester 602074 (Clark Chan, et al. Clinical Pharmaco-kinetics of Alamifovir and Its Metabolites. Antivicrob Agents Chemother, 2005, 49(5):1813-1822), while the cytotoxicity of the monoester 602074 (CC50=548 μM) is significantly higher than that of MCC-478 and 602076 (both having CC50>1000 μM) (Kamiya N, et al. Antiviral activities of MCC-478, a novel and specific inhibitor of hepatitis B Virus. Antimicrob Agents Chemother 2002; 46(9):2872).
Currently, there is still a need to find a novel drug for clinical use which is effective against viruses such as hepatitis B virus, and especially has a high bioavailability.